16 alpha, 17 alpha-acetal and ketal derivatives of 16 alpha, 17 alpha-dihydroxyprogesterone



United States Patent 16a,17a-ACETAL AND KETAL DERIVATIVES OF 16a,17d-DIHYDROXYPROGESTERONE Josef Fried, Princeton, N.J., assignor to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Nov. 18, 1958, Ser. No. 774,607 7 Claims. (Cl. 260-23955) wherein P is hydrogen, a lower alkyl radical, a monocyclic aromatic radical, a monocyclic aromatic lower alkyl radical, a monocyclic heterocyclic radical, or a monocyclic heterocyclic lower alkyl radical; Q is a monocyclic aromatic radical, a monocyclic aromatic lower alkyl radical, a monocyclic heterocyclic radical, or a monocyclic heterocyclic lower alkyl radical; or together P and Q is a heteroyclic radical.

The compounds of this invention are prepared by interacting 16u,l7u-dihydroxyprogesterone with an aldehyde or ketone of the formula:

Q a y wherein P andQ are as above-defined, and recovering the resultant acetal or ketal derivative. The. reaction is preferably carried out by treating a suspension or solution of the steroid in'the aldehyde or ketone (or an organic solvent if the aldehyde or ketone is a solid) with an acid catalyst (e.g., perchloric acid, p-toluenesulfom'e acid, hydrochloric acid, etc.) neutralizing the acid and recovering the acetal or ketal derivative formed.

Suitable aldehyde and ketone reactants include monocyclic aromatic aldehydes such as benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde), lower alkoxy benzaldehydes (e.g. o-anisaldehyde), di(lower alkoxy)- benzaldehydes (e.g. veratraldehyde), hydroxybenzaldehydes (e.g. salicylaldehyde), dihydroxy-benzaldehydes (e.g. resorcylaldehyde), lower alkyl benzaldehydes (e.g. m-tolualdehyde and p-ethylbenzaldehyde), di(lowcr alkyl)benzaldehydes (e.g. o-p-dimethylbenzaldehyde), ni-

trobenzaldehydes, acylamidobenzaldehydes (e.g. N- acetylanthranilaldehyde) and cyanobenzaldehydes; monocyclic aromatic lower alkanals, such as phenylacetaldehyde, wphenylpropionaldehyde, fi-phenylpropionaldehyde, 'y-phenylbutyraldehyde, and aromatically-substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic 2,941,997 Patented June 21, 1960,

heterocyclic aldeydes, such as alloxane, picolinaldehydes, furfural, thiophene carbonals, and halo, lower alkoxy, hydroxy, lower alkyl, nitro, and cyano derivatives there of; and monocyclic heterocyclic lower alkanals; monocylic aromatic ketones, such as acetop henone, propiophenone, butyrophenone, valerophenoue, isocaprophenone, halophenyl lower alkyl ketones (e.g. p-chloroacet0- phenone), (lower alkoxy)p henyl lower alkyl ketones (e.g. p-anisyl methyl ketone), di(lower alkoxy)phenyl lower alkyl ketones, hydroxyphenyl lower alkyl ketones,

dihydroxyphenyl lower alkyl ketones (e.g. resacetophenone), (lower alkyl) phenyl lower alkyl ketones (e.g. methyl p-tolyl ketone), di(lower alkyl)phenyl ,lower alkyl ketones (o,p-xylyl methyl ketone), nitrophenyl lower alkyl ketones (e.g. nitroacetophenone), acylamido- H phenyl loweralkyl ketones (e.g. acetylanilines), and

cyanophenyl lower alkyl ketones; benzophenone, and mono or bis substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic aromatic lower alleanones, such as 1-phenyl-3-butanone and l-phenylA-pentanone, and aro matically substituted derivatives thereof; monocyclic heterocyclic ketones, such as Z-acetyl-furan, Z-benzoyl furan, and 2-acetylthiophene; and monocyclic heterocyclic lower alkanones.

All of the compounds of this invention are physiologically-active substances which possess progestational activity when administered both in the form of tablets and as a solution or suspension and hence can be used in lieu of known progestational agents suchas progesterone in the treatment of habitual abortion for which purpose they can be administered in the same manner as progesterone, for example, the dosage being adjusted forthe relative potency of the particular steroid. This group of steroids, however, is most effective when used perorally in the form of tablets. r

The following examples are illustrative of the invention (all temperaturesbeing in centigrade):

EXAMPLE 1 To a suspension of 500 mg. of l6a,l7a-dihydroxy progesterone in 25 ml. of freshly redistilled acetophenone is added .125 ml. of 72% perchloric acid and the mixture is agitated= at room temperaturefor one hour. The clear solution is washed with dilute sodium bicarbonate toremove excess acid and the acetophenone layer, after addition of chloroform is separated from the aqueous phase. The organic layer is dried over sodium sulfate and after removal of the chloroform and acetophenone in high vacuum the residue is crystallized from alcohol. The pure acetophenone derivative has the following properties: M.P. about 142-144", [a];, +43 '(c, .50 in chloroform),

P 5.86, 5.97, 6.18, 13.18, 14.36 mu max Analysis.-Calcd for C H O (448.58): C, 77.64; H, 8.09. Found: C, 77.65; H, 7.84.

EXAMPLE 2 p-Chloroacetophenone derivative of 16a,17adihydroxyprogesrerone drying over sodium sulfate the chloroform and p-chloroacetophenone is removed in high vacuum. The resulting residue is dissolved in hexane and chromatographed on 20 grams of acid-washed alumina. Elution with hexane removes residual p-chloroacetophenone, while subsequent elution with benzene (1,000 ml.) produces the pure p-chloroacetophenone derivative, which after recrystallization from acetone-hexane has the following properties: MLP. about 1611 62.; [e1 +26 (c, 1.12 in'chloroform); I 53: 221 m (e=l9,000) 240 m (e=16,000) my 5.84, I I 6.01, 6.19, 6.70

Analysis. -Calcd for C H O Cl (483.02):' C, 72.09; H, 7.51; CI, 7.33. Found: C, 71.97; H, 7.58; Cl, 7.47.

EXAMPLE 3 p-Nitroacetophenone derivative of 160;,17a-

dihydroxyproge'sterone EXAMPLE 4 i Berizaldehyde derivative of 16a,1 7..-. dihydroxyprogesterone ",To a suspension of 100' mg. of IGaJ'Ia-(lillYdI'QXY-j progesterone in 1-5 ml. of benzaldehyde is added 0.05 ml. of 72% perchloric acid. The mixture is treated'as and Q is monocyclic aromatic.

in Example 1 and results in'the formation of the benzaldehyde derivative of 16m,17a-dihydroxyprogesterone.

V V EXAMPLES i Furfural derivative of 160e,] 7u-dihydr0xypr0gester0ne g: xAMPL s Be'nzophenone'derivative 0f"16a,1'.7a-dia hydroxyprageslerone Treatment of the. 16 ,17a-dihydroxyprogesterone with benxophenoneas; described in Example 1 furnishes the benzophenone derivative of l 6a,l7a-dihydroxyprogesterone; EXAMPLE 7 Z-acetyljuran derivative of :,17oc-dihydroxyprogesterone wherein P is selected from the group consisting of hy drogen, lower alkyl, monocylic aromatic and monocyclic aromatic lower alkyl; Q is selected from the group consisting of monocyclic aromatic, monocyclic aromatic lower alkyl, monocyclic heterocylic, and monocyclic heterocyclic lower alkylradical; and together P and Q is heterocyclic. Y

2. The steroid of claim 1, wherein P is lower alkyl 3. The acetophenone derivativei of 16u,17a-dihydroxyprogesterone.

4. The p-chloroacetophenone derivativeof 160:,17a-dihydroxyprogesterone. v I I p 7 5. The p-nitroacetophenone derivative of- 16a,17 .-dihydroxyprogesterone. 7 g

6. The benzophenone derivative of l6u,l7a-'dihydroxyprogesterone. V I T I 7."[he Z-acetylfuran derivative of 1 6oi-,17ni-dihydroxyprogesterone. j

References Cited in the file of thispatent it i 1 UNITED STATES PATENTS p 2,584,271 Hufiman Feb. 5,1)52

2,736,732 Knowles Feb. 28,1956

OTHER REFERENCES Cooley et al.: J. Chem. Soc. (December 1955), pages 

1. A STEROID OF THE GENERAL FORMULA 